Publications
518 results found
Brenner N, Mentzer AJ, Butt J, et al., 2019, Validation of multiplex Serology for human hepatitis viruses B and C, human T-lymphotropic virus 1 and Toxoplasma gondii, PLoS ONE, Vol: 14, ISSN: 1932-6203
Multiplex Serology is a high-throughput technology developed to simultaneously measure specific serum antibodies against multiple pathogens in one reaction vessel. Serological assays for hepatitis B (HBV) and C (HCV) viruses, human T-lymphotropic virus 1 (HTLV-1) and the protozoan parasite Toxoplasma gondii (T. gondii) were developed and validated against established reference assays. For each pathogen, between 3 and 5 specific antigens were recombinantly expressed as GST-tag fusion proteins in Escherichia coli and tested in Monoplex Serology, i.e. assays restricted to the antigens from one particular pathogen. For each of the four pathogen-specific Monoplex assays, overall seropositivity was defined using two pathogen-specific antigens. In the case of HBV Monoplex Serology, the detection of past natural HBV infection was validated based on two independent reference panels resulting in sensitivities of 92.3% and 93.0%, and specificities of 100% in both panels. Validation of HCV and HTLV-1 Monoplex Serology resulted in sensitivities of 98.0% and 95.0%, and specificities of 96.2% and 100.0%, respectively. The Monoplex Serology assay for T. gondii was validated with a sensitivity of 91.2% and specificity of 92.0%. The developed Monoplex Serology assays largely retained their characteristics when they were included in a multiplex panel (i.e. Multiplex Serology), containing additional antigens from a broad range of other pathogens. Thus HBV, HCV, HTLV-1 and T. gondii Monoplex Serology assays can efficiently be incorporated into Multiplex Serology panels tailored for application in seroepidemiological studies.
Kagdi HH, Taylor GP, 2018, Transcriptome and Somatic Mutation Associated with Non-Malignant Human T Lymphotropic Virus Type 1 Infection and Adult T-Cell Leukemia/Lymphoma, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Kagdi HH, Taylor GP, 2018, The In Vivo infected Clones Have Mixed Immunophenotype and Malignant Transformation Is Characterized By Dominant Growth of CD4+CCR4+CD26-CD7-Cells in Human T Lymphotropic Virus Type 1 Infection, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Rosadas C, Malik B, Taylor GP, et al., 2018, Estimation of HTLV-1 vertical transmission cases in Brazil per annum, PLoS Neglected Tropical Diseases, Vol: 12, ISSN: 1935-2727
BackgroundBrazil has at least 800,000 HTLV-1 infected individuals. HTLV-1 can be transmitted via sexual intercourse, contact with blood and from mother to child, mainly by breastfeeding. Treatments for the high morbidity/mortality associated diseases (ATL and HAM/TSP) are limited, therefore, infection prevention is of utmost importance. However, antenatal screening is not routinely performed in Brazil. A lack of data regarding the number of individuals infected via breastfeeding impairs the development of government policies. The objective is to estimate the number of HTLV-1 infections occurring annually due to mother to child transmission (MTCT) in Brazil, nationally and regionally.MethodologyTo estimate HTLV-1 MTCT in Brazil the following variables are modelled: number of births, prevalence of HTLV-1 infection in pregnant women, breastfeeding duration rate and transmission risk according to breastfeeding period. The number of cases of HAM/TSP and ATL attributable to MTCT are also estimated.Principal findingsIn 2008, there were 2,934,828 live births in Brazil. HTLV prevalence in pregnant women in Brazil ranges between 0.1–1.05% by region. An estimated 16,548 HTLV-1 infected women are pregnant each year. According to the breastfeeding pattern and HTLV-1 prevalence of each region there are an estimated 3,024 new cases of HTLV-1 infection due to MTCT annually of which 2,610 are preventable through infant feeding advice. These 3,024 transmissions will result in 120–604 cases of ATL and 8–272 of HAM/TSP. North-East region comprises the high number of MTCT cases, followed by South-East.Conclusions/significanceA high number of new HTLV-1 infections due to MTCT occur every year in Brazil. Antenatal screening and avoiding breastfeeding are essential to prevent subsequent development of HTLV-1-associated diseases.
Bangham CRM, Taylor GP, Klose RJ, et al., 2018, Histone H2A mono-ubiquitylation and p38-MAP Kinases regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1, Journal of Clinical Investigation, Vol: 3, ISSN: 0021-9738
It is not understood how the human T cell leukemia virus human T-lymphotropic virus-1 (HTLV-1), a retrovirus, regulates the in vivo balance between transcriptional latency and reactivation. The HTLV-1 proviral plus-strand is typically transcriptionally silent in freshly isolated peripheral blood mononuclear cells from infected individuals, but after short-term ex vivo culture, there is a strong, spontaneous burst of proviral plus-strand transcription. Here, we demonstrate that proviral reactivation in freshly isolated, naturally infected primary CD4+ T cells has 3 key attributes characteristic of an immediate-early gene. Plus-strand transcription is p38-MAPK dependent and is not inhibited by protein synthesis inhibitors. Ubiquitylation of histone H2A (H2AK119ub1), a signature of polycomb repressive complex-1 (PRC1), is enriched at the latent HTLV-1 provirus, and immediate-early proviral reactivation is associated with rapid deubiquitylation of H2A at the provirus. Inhibition of deubiquitylation by the deubiquitinase (DUB) inhibitor PR619 reverses H2AK119ub1 depletion and strongly inhibits plus-strand transcription. We conclude that the HTLV-1 proviral plus-strand is regulated with characteristics of a cellular immediate-early gene, with a PRC1-dependent bivalent promoter sensitive to p38-MAPK signaling. Finally, we compare the epigenetic signatures of p38-MAPK inhibition, DUB inhibition, and glucose deprivation at the HTLV-1 provirus, and we show that these pathways act as independent checkpoints regulating proviral reactivation from latency.
Hedberg ST, Eriksson L, Demontis MA, et al., 2018, Droplet digital PCR for absolute quantification of proviral load of human T-cell lymphotropic virus (HTLV) types 1 and 2, Journal of Virological Methods, Vol: 260, Pages: 70-74, ISSN: 0166-0934
BackgroundHuman T-lymphotrophic virus (HTLV) types 1 and 2 cause lifelong infection whereby most infected individuals are asymptomatic whilst a minority develop infection-related disease. These latter patients invariably have been found to have high proviral load (PVL). Therefore, infected patients are monitored by determining the proportion of lymphocytes that are infected with HTLV-1/2. An increase in PVL has been shown to represent an increasing risk of developing HTLV-associated diseases. Monitoring of PVL requires a reliable and sensitive method. In this study assays based on droplet digital PCR (ddPCR) were established and evaluated for detection and quantification of HTLV-1/2.ObjectivesTo develop two parallel assays to detect the tax genes and determine the PVL of HTLV-1 and -2.Study designSixty-seven clinical samples from patients infected with HTLV-1 or HTLV-2 were analysed. The samples had previously been analysed with a qPCR and a comparison between ddPCR and qPCR was performed. The specificity of the assays were determined by analyzing samples from 20 healthy blood donors.ResultsThe ddPCR was a stable and sensitive method for detection and quantification of HTLV-1 and -2. When comparing the qPCR and ddPCR the correlation was high (Pearsons correlation coefficient 0.96). The variability of the ddPCR was very low with intra-assay coefficient of variation (CV) of 0.97–3.3% (HTLV-1) and 1.7–8.2% (HTLV-2) and inter-assay CV of 1.8–6.1% (HTLV-1) and 1.2–12.9% (HTLV-2).ConclusionsThe ddPCR reliably quantified HTLV DNA in clinical samples and could be a useful tool for monitoring of PVLs in HTLV-infected individuals.
Kemp HI, Rice AS, Adonis A, et al., 2018, Human T-Lymphotrophic Virus - a neglected cause of chronic pain?, PAIN, Vol: 159, Pages: 1433-1437, ISSN: 0304-3959
Tosswill JHC, Taylor GP, 2018, Interpretation of low reactivity in the Abbott architect rHTLV I/II assay, Transfusion Medicine, Vol: 28, Pages: 326-330, ISSN: 1365-3148
ObjectiveThe objective of this study is to reduce donor tissue wastage.AimThe aim of this study is to determine, in the case of the Abbott Architect rHTLV I/II assay, whether a signal/cut‐off (S/CO) ratio higher than the manufacturer's recommendation of 1·0 could be applied to diagnose significant HTLV‐1 seroreactivity.BackgroundThe detection of human T cell leukaemia virus type 1 (HTLV‐1) infection is primarily based on serology often utilising random access platforms. Although current assays have high sensitivity and specificity, in low‐prevalence regions, significant numbers of false‐positive reactions occur. A comprehensive follow‐up is difficult within the time frame of organ donation. This can lead to donor tissue wastage.MethodsA retrospective analysis of 12 250 samples previously tested on the Abbott Architect rHTLV I/II platform and further tested by confirmatory serology/molecular detection to determine the sensitivity and positive predictive value in the S/CO ratio range was conducted.ResultsWhere the sample S/CO ratio was >20 (n = 498), HTLV infection was confirmed in all but eight subjects. All of these eight had indeterminate confirmatory results, and none were found to be uninfected. Conversely, in the samples within the S/CO ratio range 1–4 (n = 271), no subject was subsequently found to be HTLV‐infected although HTLV infection could not be excluded in all cases, primarily due to lack of follow‐up samples (n = 60/271).ConclusionsSamples with an S/CO ratio of <4·0 on the Abbott Architect rHTLV I/II platform represent a low risk of HTLV infection in the UK, and organs from such donors might reasonably be considered for transplantation, within the context of appropriate risk–benefit assessment.
Katsuya H, Cook LB, Rowan A, et al., 2018, Phosphatidylinositol 3-kinase-delta (PI3K-delta) is a potential therapeutic target in adult T-cell leukemia-lymphoma, Biomarker Research, Vol: 6, ISSN: 2050-7771
The prognosis of adult T-cell leukemia-lymphoma (ATL) remains very poor, and there is an urgent clinical need to investigate novel therapies for ATL. The expression of phosphatidylinositol 3-kinase-δ (PI3k-δ) is normally restricted to hematopoietic cells and is known as a key determinant of cell survival in certain cancers. The inhibitor of PI3k-δ, idelalisib, has been shown to be effective in the treatment of chronic lymphocytic leukemia. Here, we report the expression of PI3k-δ and the ability of idelalisib to promote apoptosis in ex vivo ATL samples. The activity of PI3K was quantified by a PI3-Kinase Activity ELISA kit. Although there was no significant difference in mean PI3K activity between healthy donors and patients with ATL, certain cases of ATL showed extremely high PI3K activities. The expression of PI3k-δ protein was detectable in most ATL cases. The freshly isolated cells from ATL patients were cultured with or without idelalisib for 0–10 days, and cell survival was then quantified. Idelalisib induced apoptosis in ATL cells in a time-dependent manner, and significantly reduced the frequency of viable ATL cells at 10 days. No time-dependent effects of idelalisib were observed in non-malignant T cells from the same patients. CCL22 has been reported to promote survival of ATL cells in part through the PI3K-AKT pathway. Idelalisib blocked this CCL22-induced phosphorylation of AKT and significantly inhibited the proliferation of ATL cells. These results validate the PI3K-AKT pathway as a potential therapeutic target in ATL.
Short CS, Quinlan R, Bennett P, et al., 2018, Optimising the collection of female genital tract fluid for cytokine analysis in pregnant women, Journal of Immunological Methods, Vol: 458, Pages: 15-20, ISSN: 0022-1759
Introduction: To better understand the immunology of pregnancy, study of female genital tract fluid (FGF) is desirable. However the optimum method of collection of FGF in pregnant women for immunological methods, specifically cytokine measurement, is unknown.Methods:A prospective study of HIV-uninfected pregnant women comparing two methods of FGF collection: polyvinyl acetal sponge collection of cervical fluid (CF) and menstrual cup collection of cervicovaginal fluid (CVF). Samples were collected at 3 time points across the second and third trimesters: 14-21, 22-25 and 26-31 weeks. Multiplex chemi-luminescent assays were used to measure: IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13 and TNF-α. Optimal methodology for cytokine normalisation (sample weight, volume and total protein) was explored. ResultsAll cytokines were measurable in both fluid types. IL-1β, IL-8 and IL-6 were detected at the highest concentrations (ranking order CF > CVF > plasma). CVF collection was simpler, provided the largest volume of sample (median 0.5g) with the potential for undiluted usage, and allowed for self-insertion. CF cytokine concentrations were intrinsically associated with sample weight and protein concentration however CVF cytokines were independent of these. Conclusion:Both methods of collection are robust for measurement of FGF cytokines during pregnancy. We recommend CVF collection using a menstrual cup as a viable option in pregnant women for high dimensional biological techniques.
Foster C, Fidler S, Lyall E, et al., 2018, Careful consideration when responding to new data: dolutegravir and pregnancy, Journal of virus eradication, Vol: 4, Pages: 208-208, ISSN: 2055-6640
This case highlights the current complexities of managing women in the early stages of pregnancy presenting on dolutegravir-based regimens. When responding to new data, there is an important decision to be made, between the potential, uncertain risk of teratogenicity against the potential increased risk of in utero vertical transmission of HIV-1.
Crawshaw AA, Dhasmana D, Jones B, et al., 2018, Human T-cell lymphotropic virus (HTLV)-associated encephalopathy: an under-recognised cause of acute encephalitis? Case series and literature review, Journal of Neurology, Vol: 265, Pages: 871-879, ISSN: 0340-5354
Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) is well described. Clinical features are predominantly consistent with cord pathology, though imaging and autopsy studies also demonstrate brain inflammation. In general, this is subclinical; however, six cases have previously been reported of encephalopathy in HTLV-1-infected patients, without alternative identified aetiology. We describe three further cases of encephalitis in the UK HAM cohort (n = 142), whereas the annual incidence of acute encephalitis in the general population is 0.07-12.6 per 100,000. Clinical features included reduced consciousness, fever/hypothermia, headaches, seizures, and focal neurology. Investigation showed: raised CSF protein; pleocytosis; raised CSF:peripheral blood mononuclear cell HTLV-1 proviral load ratio; and MRI either normal or showing white matter changes in brain and cord. Four of the six previous case reports of encephalopathy in HTLV-infected patients also had HAM. Histopathology, reported in three, showed perivascular predominantly CD8+ lymphocytic infiltrates in the brain. One had cerebral demyelination, and all had cord demyelination. We have reviewed the existing six cases in the literature, together with our three new cases. In all seven with HAM, the spastic paraparesis deteriorated sub-acutely preceding encephalitis. Eight of the nine were female, and four of the seven treated with steroids improved. We propose that HTLV-associated encephalopathy may be part of the spectrum of HTLV-1-induced central nervous system disease.
Fidler S, Brown C, Khan M, et al., 2018, Adapting HIV testing algorithms and clinical advice for people with persistently indeterminate test results: The Indeterminate Retrovirus Infection Service (IDRIS), Publisher: WILEY, Pages: S96-S96, ISSN: 1464-2662
Kagdi H, Demontis MA, Ramos JC, et al., 2018, Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection, PLoS Pathogens, Vol: 14, ISSN: 1553-7366
Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed to disease-associated immune suppression. ATL cells have a CD4+CCR4+CD26-CD7- immunophenotype but infected cells with this immunophenotype ('ATL-like' cells) are also present in non-malignant HTLV-1 infection. We hypothesized that 'ATL-like' and ATL cells have distinct cytokine producing capacity and a switch in the cytokines produced occurs during leukemogenesis. Seventeen asymptomatic carriers (ACs), 28 patients with HTLV-1-associated myelopathy (HAM) and 28 with ATL were studied. Plasma IL-10 concentration and the absolute frequency of IL-10-producing CD4+ T cells were significantly higher in patients with ATL compared to AC. IL-10-producing ATL cells were significantly more frequent than 'ATL-like' cells. The cytokine-producing cells were only a small fraction of ATL cells. Clonality analysis revealed that even in patients with ATL the ATL cells were composed not only of a single dominant clone (putative ATL cells) but also tens of non-dominant infected clones ('ATL-like' cells). The frequency of cytokine-producing cells showed a strong inverse correlation with the relative abundance of the largest clone in ATL cells suggesting that the putative ATL cells were cytokine non-producing and that the 'ATL-like' cells were the primary cytokine producers. These findings were confirmed by RNAseq with cytokine mRNA expression in ATL cells in patients with ATL (confirmed to be composed of both putative ATL and 'ATL-like' cells by TCR analysis) significantly lower compared to 'ATL-like' cells in patients with non-malignant HTLV-1 infection (confirmed to be composed of hundreds of non-dominant clones by TCR analysis). A significant inverse correlation between
Taylor GP, 2018, Human T-Lymphotropic Virus Type 1 infection and solid organ transplantation, Reviews in Medical Virology, Vol: 28, Pages: e1970-e1970, ISSN: 1052-9276
HTLV infection appears to be more common among renal transplant candidates than in the related general population. HTLV‐1‐associated diseases may occur in carriers who are transplanted but there is insufficient evidence to confirm whether these occur more frequently as a result of the associated immunosuppression. Consequently, pre‐existing HTLV‐1 infection should not be considered a contra‐indication to transplantation.The risk of transmission of HTLV‐1 through solid organ transplantation from a confirmed infected donor is unknown. There are anecdotes of multiple infections from a single donor. Biologically due to the significant volume of blood and the lack of storage, transmission would be expected to be higher than following blood transfusion. The rate of subsequent disease is unknown, but there are now 11 reports of HAM and 2 of ATL occurring within 4 years of transplantation associated infection. There are insufficient data to know whether the time from infection to onset of disease and the rate of progression differ from transmission through other routes, but early onset and rapid progression is a concern. Responses to enhanced immunosuppression for the treatment of HAM are variable.The risk of HTLV‐1 associated disease in exchange for a life‐saving major organ transplantation from an infected donor might be considered worth taking by some HTLV‐1 uninfected patients. Peri‐transplantation antiretroviral prophylaxis with zidovudine and raltegravir is biologically sound but therapeutically unproven. The risks related to HTLV‐1 infection appear to preclude the use of any other tissue. All transplant donors should be screened for HTLV‐1 infection regardless of perceived risk.
Einsiedel L, Purcell D, Schinke S, et al., 2018, Highlights from the HTLV-1 symposium at the 2017 Australasian HIV and AIDS Conference held jointly with the 2017 Australasian Sexual Health Conference, November 2017, Canberra, Australia, JOURNAL OF VIRUS ERADICATION, Vol: 4, Pages: 48-50, ISSN: 2055-6640
Favarato G, Townsend CL, Bailey H, et al., 2017, Protease inhibitors and preterm delivery: another piece in the puzzle., AIDS, Vol: 32, Pages: 243-252, ISSN: 0269-9370
BACKGROUND: Questions remain regarding preterm delivery (PTD) risk in HIV-infected women on antiretroviral therapy (ART), including the role of ritonavir-boosted protease inhibitors (PI/r), timing of ART initiation and immune status. METHODS: We examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood on women with HIV delivering a singleton live infant in 2007-2015, including those pregnancies receiving PI/r-based (n=4184) or non-nucleoside reverse transcriptase inhibitors (NNRTI)-based regimens (n = 1889).We conducted logistic regression analysis adjusted for risk factors associated with PTD and stratified by ART at conception and CD4 count to minimise bias by indication for treatment and to assess whether PTD risk differs by ART class and specific drug combinations. RESULTS: Among women conceiving on ART, lopinavir/ritonavir was associated with increased PTD risk in those with CD4 ≤350 (aOR 1.99[1.02, 3.85]) and with CD4>350 (aOR 1.61[1.07, 2.43]) versus women on NNRTI-based (mainly efavirenz and nevirapine) regimens in the same CD4 sub-group. Associations between other PI-based regimens (mainly atazanavir and darunavir) and PTD risk were complex. Overall, PTD risk was higher in women who conceived on ART, had low CD4 countand were older. No trend of association of PTD with tenofovir or any specific drug combinations were observed. CONCLUSIONS: Our data support a link between the initiation of ritonavir-boosted/lopinavir-based ART pre-conception and PTD in subsequent pregnancies, with implications for treatment guidelines. Continued monitoring of PTD risk is needed as increasing numbers of pregnancies are conceived on new drugs.
Cook LB, Rowan A, Demontis M, et al., 2017, Long-term clinical remission maintained after cessation of zidovudine and interferon-α therapy in chronic adult T-cell leukemia/lymphoma, International Journal of Hematology, Vol: 107, Pages: 378-382, ISSN: 0925-5710
Globally, > 5–10 million people are estimated to be infected with Human T-lymphotropic virus type 1 (HTLV-1), of whom ~ 5% develop adult T-cell leukemia/lymphoma (ATL). Despite advances in chemotherapy, overall survival (OS) has not improved in the 35 years since HTLV-1 was first described. In Europe/USA, combination treatment with zidovudine and interferon-α (ZDV/IFN-α) has substantially changed the management of patients with the leukemic subtypes of ATL (acute or unfavorable chronic ATL) and is under clinical trial evaluation in Japan. However, there is only a single published report of long-term clinical remission on discontinuing ZDV/IFN-α therapy and the optimal duration of treatment is unknown. Anecdotal cases where therapy is discontinued due to side effects or compliance have been associated with rapid disease relapse, and it has been widely accepted that the majority of patients will require life-long therapy. The development of molecular methods to quantify minimal residual disease is essential to potentially guide therapy for individual patients. Here, for the first time, we report molecular evidence that supports long-term clinical remission in a patient who was previously treated with ZDV/IFN-α for 5 years, and who has now been off all therapy for over 6 years.
Kulkarni A, Mateus M, Thinnes CC, et al., 2017, Glucose metabolism and oxygen availability govern reactivation from latency of the human retrovirus HTLV-1, Cell Chemical Biology, Vol: 24, Pages: 1377-1387.e3, ISSN: 2451-9456
The human retrovirus HTLV-1 causes a hematological malignancy or neuroinflammatory disease in ∼10% of infected individuals. HTLV-1 primarily infects CD4+ T lymphocytes and persists as a provirus integrated in their genome. HTLV-1 appears transcriptionally latent in freshly isolated cells; however, the chronically active anti-HTLV-1 cytotoxic T cell response observed in infected individuals indicates frequent proviral expression in vivo. The kinetics and regulation of HTLV-1 proviral expression in vivo are poorly understood. By using hypoxia, small-molecule hypoxia mimics, and inhibitors of specific metabolic pathways, we show that physiologically relevant levels of hypoxia, as routinely encountered by circulating T cells in the lymphoid organs and bone marrow, significantly enhance HTLV-1 reactivation from latency. Furthermore, culturing naturally infected CD4+ T cells in glucose-free medium or chemical inhibition of glycolysis or the mitochondrial electron transport chain strongly suppresses HTLV-1 plus-strand transcription. We conclude that glucose metabolism and oxygen tension regulate HTLV-1 proviral latency and reactivation in vivo.
Siemieniuk RAC, Lytvyn L, Mah Ming J, et al., 2017, Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline, British Medical Journal, Vol: 358, ISSN: 0959-8138
Ireland G, Croxford S, Tosswill JHC, et al., 2017, Human T-lymphotropic viruses (HTLV) in England and Wales, 2004-2013: Testing and diagnoses, Eurosurveillance, Vol: 25, ISSN: 1560-7917
Human T-lymphotropic virus (HTLV) infection has been under enhanced surveillance in England and Wales since 2002, however, little is known about testing patterns. Using data from two surveillance systems held at Public Health England, we described HTLV antibody testing patterns between 2008 and 2013 and the demographic and clinical characteristics of persons diagnosed with HTLV in England and Wales between 2004 and 2013. An increase in HTLV testing was observed in England between 2008 and 2013 (3,581 to 7,130). Most tests (82%; 7,597/9,302) occurred within secondary care, 0.5% (48/9,302) of persons were reactive for HTLV antibodies and 0.3% (27/9,302) were confirmed positive. Increasing age and female sex were predictors of a reactive HTLV screen and confirmed diagnosis. Testing in primary care including sexual health and antenatal services was infrequent. Between 2004 and 2013, 858 people were diagnosed with HTLV, most of whom were female (65%; 549/851), of black Caribbean ethnicity (60%), not born in the United Kingdom (72%; 369/514) and asymptomatic at diagnosis (45%; 267/595). Despite increased testing, the epidemiology and clinical features of those diagnosed with HTLV have remained consistent. Apart from donor screening, testing for HTLV infection remains uncommon, except to diagnose associated disease.
Dhasmana D, Puri A, Buell K, et al., 2017, Impact of HTLV-1 co-infection on T cells in patients with fully suppressed HIV infection: an open, single centre, cross-sectional study, Publisher: WILEY, Pages: 10-10, ISSN: 1464-2662
Nunes D, Boa-Sorte N, Rios Grassi MF, et al., 2017, HTLV-1 is predominantly sexually transmitted in Salvador, the city with the highest HTLV-1 prevalence in Brazil, PLOS ONE, Vol: 12, ISSN: 1932-6203
Background:Salvador is the city with the highest number of HTLV-1 infected individuals in Brazil, yet the main route of HTLV-1 transmission is unknown.Objective:To investigate the association of syphilis infection as a proxy for sexual transmission of HTLV-1 infection in the general population of this city.Methods:A cross sectional population-based study was conducted with 3,451 serum samples obtained by a representative simple random sampling. Data on gender, age, income, and years of education were collected by questionnaire and the presence of HTLV, HIV and Treponema pallidum infection was determined by serology. Logistic regression analysis was used to evaluate the independent effect of the potential explanatory variables to HTLV-1 infection and Odds Ratios (OR) and 95% CI were calculated.Results:The majority of studied individuals were female (56.4%), had less than 7 years of education (55.3%) and earned two or less minimum wages (52.0%). The overall prevalence of HTLV-1 was 1.48% (51/3,451; 95% CI: 1.10%– 1.94%), which increased with age. Only three persons younger than 17 (3/958; 0.31%; CI 95% 0.06–0.91) years were infected by HTLV-1. Among the 45 syphilis positives, 12 (26.7%) were HTLV positive, while among 21 HIV positives, only one (4.8%) was HTLV positive. HTLV-1 infection was found to be associated with syphilis infection (ORADJUSTED 36.77; 95% CI 14.96–90.41).Conclusion:The data presented herein indicate that horizontal transmission between adults is the main route of HTLV-1 infection in the general population of Salvador and that this is likely to occur through sexual contact.
Kagdi HH, taylor GPT, DEMONTIS MA, et al., 2016, Risk stratification of adult T cell leukemia/lymphoma using immunophenotyping, Cancer Medicine, Vol: 6, Pages: 298-309, ISSN: 2045-7634
Adult T cell leukemia/lymphoma (ATL), a human T lymphotropic virus type 1 (HTLV-1) –associated disease, has a highly variable clinical course and four subtypes with therapeutic and prognostic implications. However, there are overlapping features between ATL subtypes and between ATL and non-malignant (non-ATL) HTLV-1 infection complicating diagnosis and prognostication. To further refine the diagnosis and prognosis of ATL we characterized the immunophenotype of HTLV-1-infected cells in ATL and non-ATL. A retrospective study of peripheral blood samples from ten HTLV-1-uninfected subjects (UI), 54 HTLV-1infected patients with non-ATL and 22 with ATL was performed using flow cytometry. All patients with ATL had CD4+CCR4+CD26- immunophenotype and the frequency of CD4+CCR4+CD26- T cells correlated highly significantly with the proviral load in non-ATL suggesting CD4+CCR4+CD26- as a marker of HTLV-1 infected cells. Further immunophenotyping of CD4+CCR4+CD26- cells revealed that 95% patients with ATL had a CD7- (≤ 30% CD7+ cells) whereas 95% HTLV+ non-ATL had CD7+ (>30% CD7+ cells) immunophenotype. All patients with aggressive ATL had a CCR7+ (≥30%), whereas 92 % with indolent ATL and 100% non-ATL had a CCR7- (<30%) immunophenotype. Patients with non-progressing indolent ATL were CD127+ but those with progressive lymphocytosis requiring systemic therapy had a CD127- (≤ 30%) immunophenotype. In summary, HTLV-1-infected cells have a CD4+CCR4+CD26- immunophenotype. Within this population, CD7- phenotype suggests a diagnosis of ATL, CCR7+ phenotype identifies aggressive ATL, while CCR7- CD127- phenotype identifies progressive indolent ATL.
Gallo RC, Willems L, Hasegawa H, et al., 2016, Screening transplant donors for HTLV-1 and -2, Blood, Vol: 128, Pages: 3029-3031, ISSN: 1528-0020
Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus discovered in 1980.1 HTLV-1 causes 2 devastating diseases: adult T-cell leukemia/lymphoma (ATL) and a neurological disorder, HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP or, more briefly, HAM). ATL becomes apparent in 2% to 5% of those infected with HTLV-1; another 1% to 2% will develop HAM.2 There are usually 2 to 3 decades of latency after the infection before the onset of symptoms. A second HTLV (HTLV-2) isolated in 1982 has been causally linked to HAM, but not ATL.3In other cases, HTLV-1 and HTLV-2 infection may remain asymptomatic for years while being transmitted from person-to-person through host cells in body fluids and breast milk, blood cell transfusions, and solid organ transplantation. There are no licensed vaccines to prevent HTLV-1 or HTLV-2 infections.
Cook LB, Rowan AG, Demontis MA, et al., 2016, HTLV-1 proviral load after two months' treatment with anti-CCR4 monoclonal antibody mogamulizumab predicts a molecular response to disease and durable clinical remission in leukaemic subtypes of adult T-cell leukaemia/lymphoma, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: American Society of Hematology, Pages: 5356-5356, ISSN: 0006-4971
Phillips A, Fields P, Hermine O, et al., 2016, A prospective, multicenter, randomized study of anti-CCR4 monoclonal antibody mogamulizumab versus investigator's choice in the treatment of patients with relapsed/Refractory adult tTcell leukemia-lymphoma: overall response rate, progression-free survival, and overall survival, 58th ASH Annual Meeting and Exposition, Publisher: American Society of Hematology, Pages: 4159-4159, ISSN: 0006-4971
Dimber R, Guo Q, Bishop C, et al., 2016, Evidence of brain inflammation in patients with Human T Lymphotropic Virus type 1 associated myelopathy (HAM): A pilot, multi-modal imaging study using [11C] PBR28 PET, MR T1w and DWI, Journal of Nuclear Medicine, Vol: 57, Pages: 1905-1912, ISSN: 1535-5667
HAM is a chronic debilitating neuroinflammatory disease with a predilection for the thoraciccord. Tissue damage is attributed to the cellular immune response to HTLV-1 infectedlymphocytes. Using a specific 18KDa Translocator Protein ligand, [11C] PBR28, T1-weightedand Diffusion Weighted magnetic resonance imaging, the brains of HTLV-1 infected patients,with and without HAM but no clinical evidence of brain involvement, were examined.Methods: Five subjects with HAM and two HTLV-1 asymptomatic carriers (AC) werestudied. All underwent clinical neurological assessment including cognitive function andobjective measures of gait, quantification of HTLV-1 proviral load in peripheral bloodmononuclear cells and HLA DR expression on circulating CD8+ lymphocytes. [11C] PBR28PET and MRI were performed on the same day. [11C]PBR28 PET total volume of distribution(VT) and distribution volume ratio (DVR) were estimated using 2-tissue compartmentmodelling. MRI data was processed using tools from the FMRIB Software Library (FSL) toestimate mean diffusivity (MD) and grey matter (GM) fraction changes. The results werecompared with data from age matched healthy volunteers.Results: Across the whole brain the VT for the subjects with HAM (5.44±0.84) wassignificantly greater than those of AC (3.44±0.80). The DVR of thalamus in patients withsevere and moderate HAM were higher compared to the healthy volunteers suggestingincreased TSPO binding (z>4.72). Subjects with more severe myelopathy and with high DRexpression on CD8+ lymphocytes had increased DVR and MD (near-significant correlationfound for the right thalamus MD: p=0.06). On the T1-weighted MRI scans, the GM fractionof the brain stem was reduced in all HTLV1-infected patients compared to controls(p<0.001), whilst the thalamus GM fraction was decreased in patients with HAM andcorrelated with the disease severity. There was no correlation between neurocognitivefunction and these markers of CNS inflammation.3Conclusio
Rowan A, Witkover A, Melamed A, et al., 2016, T cell receptor Vβ staining identifies the malignant clone in adult T cell leukemia and reveals killing of leukemia cells by autologous CD8+ T cells, Plos Pathogens, Vol: 12, ISSN: 1553-7374
There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.
Willems L, Hasegawa H, Accolla R, et al., 2016, Reducing the global burden of HTLV-1 infection: an agenda for research and action, Antiviral Research, Vol: 137, Pages: 41-48, ISSN: 1872-9096
Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.
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